Pregabalin (Lyrica®) is the (S) enantiomer of 3-(aminoethyl)-5-methylhexanoic acid, structurally similar to the neurotransmitter γ-aminobutyric acid (GABA) and a successor to Gabapentin which is a neurontin drug. It is found to be potent for the treatment of neurological related disorders, epilepsy, anxiety and social phobia. Pharmacological studies show that only (S)-enantiomer is responsible for the drug activity, whereas (R)-enantiomer is inactive.

Numerous methods describing the synthesis of Pregabalin have been reported.
An Article titled, “Chemical Development of CI-1008, an Enantiomerically Pure Anticonvulsant” by Marvin S. Hoekstra, Denis M. Sobieray, Mark A. Schwindt, Thomas A. Mulhern, Todd M. Grote, Brian K. Huckabee, Valerie S. Hendrickson, Lloyd C. Franklin, Eric J. Granger, and Gregory L. Karrick in Organic Process Research & Development 1997, 1, 26-38, reports the development of a manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid, an anticonvulsant, is described. Initial preparation employed an Evans chiral alkylation on (4R,5S)-4-methyl-3-(1-oxo-4-methylpentyl)-5-phenyl-2-oxazolidinone, using benzyl bromoacetate. Use of tert-butyl bromoacetate, proved advantageous for large-scale preparation. Route selection for a low-cost manufacturing process was based on “ideal process” cost projections. Four routes were evaluated in the laboratory. Of the four, two were scaled up in the pilot plant, resulting in selection of a route based on synthesis of racemic 3-(aminomethyl)-5-methylhexanoic acid, followed by resolution with (S)-(+)-mandelic acid.
Patent no. WO 2011/141923 A2 by Lupin limited discloses a cost effective, ecofriendly process for preparation of enantiomerically pure (S)-3-cyano-5-methyl-hexanoic acid alkyl ester which is an intermediate of γ-amino acids, particularly (S)-Pregabalin.
Patent no. WO 01/55090 A1 by Warner Lambert company discloses a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin) or a salt thereof via an asymmetric hydrogenation synthesis. Article titled “An efficient total synthesis of (±) Pregabalin” by Shivajishelke et al. in Indian Journal of Chemistry Vol. 51 B, April 2012, 631-34 discloses preparation of (±) Pregabalin (80%) comprising protection and deprotection of NH2 group by Boc.
Industrially, Pregabalin is prepared using enzymatic resolution method developed by Pfizer. Alternatively, enantiomerically pure Pregabalin can be obtained using diastereomeric resolution methods, different chiral pool approaches starting from L-leucine, D-mannitol & γ-butyrolactones, etc. Further, many enantioselective routes have highlighted in the literature such as asymmetric hydrogenation using rhodium Me-DuPHOS catalyst, Quinine mediated desymmetrization of cyclic anhydride and use of chiral auxiliaries such as, Evan's oxazolidinone and (S)-methylbenzyl amine. One interesting route was developed by Jacobsen and co-workers of conjugate addition of hydrogen cyanide to α, β-unsaturated imide using aluminiumsalen catalyst. Very recently, Li et al reported the synthesis using asymmetric Michael addition of diethyl malonate and nitroalkene under solvent-free conditions using chiral thiourea catalyst. Some of these methods have intrinsic disadvantages such as expensive, commercially unavailable starting materials & catalysts, high catalytic loading, low yield, low stereoselectivity amongst others. In addition, crystallization of intermediates is often required in order to achieve high enantiopurity of final Pregabalin.
Therefore, development of a new practical and expeditious synthesis of Pregabalin is highly desirable.